NINDS Counterterrorism and Neuroscience Workshop

Workshop Summary

Rationale

The increased risk of a terrorist attack in the U.S. involving biological or chemical agents has created new challenges for many departments and agencies across the government. The NIH, with its mission to improve the health of the Nation by conducting and supporting biomedical research, is taking a leadership role in pursuing the development of new and improved medical countermeasures designed to prevent, diagnose, and treat the conditions caused by potential agents of terrorism.

Counterterrorism: Military vs. Civilian Research Needs

Biomedical research aimed at countering the effects of chemical warfare agent exposure is supported primarily through the United States Army Medical Research Institute of Chemical Defense (USAMRICD). However, USAMRICD has historically focused on developing chemical agent countermeasures to be used in the context of traditional warfare, and there are significant differences between traditional warfare and terrorism that must be considered in developing effective countermeasures:

Targeted population. The civilian population is more heterogeneous in age, health, and gender than the military population. The efficacy and safety of countermeasures may be different among selected groups within the general population.

Environment. Military attacks would most likely occur in the open air, where highly volatile compounds, like cyanide, are not fully effective. Terrorist attacks could occur in confined environs, where chemicals like cyanide present a significant threat.

Goals of the attack. Unlike a military attack, a terrorist attack does not have to cause a large number of casualties to be effective. For example, a chemical attack that compromises the food supply may kill only a few individuals but it could lead to widespread panic.

Ability to prepare. The military knows what agents are likely to be used in warfare and often can prepare for an attack; a terrorist attack may come without warning, with any number of unanticipated agents. The military focus on developing prophylactic and post-exposure treatments for a narrow range of agents may not be the ideal approach for counterterrorism research.

Access to therapy. Inhalation therapies are inappropriate for soldiers wearing gas masks, but may be effective in the general population for responding to a terrorist attack. However, IV-based therapies may not be well suited for terrorist victims, given that first responders may not have sufficient personnel or time to administer them.

Counterterrorism and Neuroscience: Role for the NINDS

Many chemical and biological agents that could serve as terrorist weapons target the nervous system. Several agents of higher priority to NINDS include traditional chemical warfare agents, like organophosphate nerve agents (e.g., sarin, VX), which disrupt cholinergic pathways and lead to seizures, muscle paralysis, and death, and blood agents (e.g., cyanide), which prevent the normal transfer of oxygen from the blood into the brain and cause headache, vertigo, and seizures. Toxic industrial chemicals (TICs) and materials (TIMs), including pesticides, also pose a threat. Biological agents of concern include neurotoxins (e.g., botulinum toxin), which cause paralysis; viral encephalitides, which can cause paralysis and convulsions; and anthrax, which can cause meningitis and cognitive deficits in survivors. The vaccinia virus, the active component of the smallpox vaccine, is associated with a rare incidence of encephalitis.

In the fall of 2002, the leadership at NINDS met with representatives from USAMRICD to discuss how NINDS might help advance counterterrorism research. Three broad research areas were identified in which NINDS expertise could be applied: persistent seizures (status epilepticus), neuroprotection, and neurodegeneration. Over the next year, NINDS continued discussions with USAMRICD to identify chemical counterterrorism research needs and to determine how best to coordinate NINDS and USAMRICD research efforts. The NINDS also participated in a workshop held by the National Institute of Allergy and Infectious Diseases (NIAID) in March 2003, which identified gaps in chemical agent-related research.

Although NINDS has long supported basic research indirectly related to chemical agents (e.g., studies on the acetylcholine pathway, epilepsy, neurodegeneration), the NINDS took the initiative in stimulating neuroscience research directly applicable to counterterrorism by soliciting administrative supplement applications in May 2003 (http://grants2.nih.gov/grants/guide/notice-files/NOT-NS-03-011.html). The supplements focus on the prevention, diagnosis, and treatment of neurological dysfunction caused by chemical and biologically-derived terrorist agents, and the mechanisms by which these agents disrupt normal neurological function. Seven supplements have been awarded as of May 2004.

Workshop Goals and Structure

The NINDS organized the April 7-8, 2004 Counterterrorism and Neuroscience Research Workshop to identify specific counterterrorism research gaps that would provide the framework for defining the goals of a research agenda, and to develop strategies for implementing this research among federal and non-federal laboratories. The workshop was also intended to stimulate interest and awareness in the NIH extramural research community of the challenges and opportunities, and to encourage discussion of potential partnerships in this research field.

To solicit a broad range of perspectives, NINDS invited speakers and participants from diverse communities, including the Department of Defense (DoD) and DoD-contract laboratories, academic neuroscience and neurology departments, the toxicology community, biotechnology industry, other NIH components, the White House Office of Science and Technology Policy, Department of Homeland Security, FDA, CDC and others. Each scientific session was co-chaired by a representative from the DoD and a representative from academia in order to promote interactions between these communities.

The Workshop included an overview of the challenges and current government efforts to address terrorist threats, four sessions focused on scientific issues, a presentation on the FDA regulatory process, and discussions of research gaps and potential research partnerships to facilitate progress. The scientific sessions covered agent-induced acute and chronic pathophysiology in the nervous system, mechanisms of agent-induced damage to the nervous system, diagnosis, and development of medical countermeasures. The discussion resulted in a draft list of research gaps and resource needs, which were subsequently refined through informal discussions with workshop participants and NINDS staff.

Research Gaps and Resource Needs

The workshop identified cross-cutting issues that should be considered in designing a counterterrorism research program, along with specific recommendations for research and resources.

Effects of exposure and underlying mechanisms

The workshop participants determined that an understanding of the effects of chemical and biological agents at the molecular, cellular, systems, and behavioral levels is needed to guide the development of safe and effective countermeasures and diagnostics.

Chemical agents pose a particular challenge in that their effects can be highly variable. The limited available data suggest that the effects of acute, high-dose chemical exposure are quite different from those associated with low dose exposure. Therefore research is needed to characterize the dose-dependent effects of chemical agents, including high-level acute to low-level chronic exposures. Furthermore, these effects may be residual (i.e., long-lasting with little or no recovery) or latent (i.e., only appearing weeks after the initial exposures) and could be affected by stress, illness, or exposure to other chemicals in the environment. The route of exposure (i.e., inhalation, ingestion, cutaneous, etc.) could also make a difference. Even in a single chemical terrorist attack, different victims could be exposed to different concentrations of the chemical, for different durations, and through different routes.

The diversity of the civilian population is another complicating factor. Most research to date on the physiological effects of chemical agents has been sponsored by the military, for the military population, which is predominantly male, young adult, and healthy. In contrast, victims of terrorist attack could also include infants, children, and the elderly; women, including those who are pregnant or nursing; and people with preexisting medical conditions. Medical conditions, such as epilepsy and neurodegenerative diseases, could conceivably exacerbate the effects of chemical exposure or limit the safety or effectiveness of available chemical countermeasures. There might be dangerous interactions between drugs taken for these conditions and treatments for chemical agent exposure (for example, cholinesterase inhibitors are used to treat Alzheimers Disease, while nerve agents and their countermeasures (e.g. pyridostigmine) also inhibit cholinesterase-the interactions between these are unknown).

While a significant amount of research is underway to understand the lethality of biological agents, the neurological sequelae observed in survivors have not been addressed. Survivors of inhalational anthrax have reported cognitive difficulties, and the vaccinia virus, used in vaccinations against smallpox, is associated with a rare incidence of encephalomyelitis (inflammation of the brain and spinal cord).

Diagnosis

Making a correct and immediate diagnosis of chemical agent exposure is crucial to delivering effective treatment. A major diagnostic challenge is that different chemicals can cause similar clinical manifestations, although the treatments for them may be different. It can even be difficult to distinguish between the effects of chemical exposure and psychological trauma, based on behavioral observation. Administering the wrong treatment due to misdiagnosis may not only be ineffective, but dangerous; some antidotes, such as the cyanide antidotes, have a low margin for safety.

Time is also of essence, as many chemical agents cause permanent injury or death within minutes. Because of the extremely short time window, diagnostic strategies must be appropriate for use by first responders, in pre-hospital settings, and must give immediate results. The diagnostic strategy must also be easy to use, as first responders typically do not have experience in working with casualties of chemical exposure.

Countermeasures

Countermeasures must be designed with the demands of responding to a terrorist attack in mind. As noted earlier, the civilian population is more diverse than the military population; countermeasures that have been approved for military use will need to be reexamined for their applicability to a broader population. Because it is unlikely that we will be able to predict what chemical might be used in a terrorist attack, the ideal chemical countermeasure would be broadly effective. Since the time and place of an attack is unpredictable, focus should be on developing post-exposure treatments, as opposed to prophylactic measures, for the general population. However, prophylactic treatments are needed for first responders and other professionals who must enter a contaminated site. As is the case for diagnostics, countermeasures need to be well-suited for use in the pre-hospital setting by first responders. Treatments that can be administered in the field to extend the effective therapeutic window, allowing the patient to survive delivery to the hospital, are also needed.

Resource needs

Validated animal models are needed to elucidate neurophysiological effects of exposure to chemical and biological agents and to test the safety and efficacy of potential countermeasures. The benefits of using non-human primates must be considered along with the costs and limited availability.

Researchers will also need access to laboratories that are certified to use chemical agents. It is necessary to use the chemical agent of interest, rather than analogs, for experiments on the effects of chemical agents. It is not known whether analogs commonly used in research successfully mimic chemical agents at molecular, cellular, or system-wide levels, especially when administered at sublethal doses.

Next Steps

The NINDS will use the list of research gaps identified during the workshop as the basis for a counterterrorism and neuroscience research agenda. The NINDS will also work with other NIH components, including the NIAID, to create a broader chemical agent biomedical research agenda that addresses the effects of chemical agents on all major systems in the body and to develop partnerships to implement this agenda.

SPEAKERS (in chronological order)

David A. Jett, Ph.D., Program Director, NINDS

Audrey S. Penn, M.D., Deputy Director, NINDS

Story C. Landis, Ph.D., Director, NINDS

Philip Edelman, M.D., Office of the Director, CDC; Senior Medical Advisor to the Assistant Secretary, Public Health Emergency Preparedness, DHHS; National Science & Technology Council, Executive Office of the President

COL James A. Romano, Jr., Ph.D., US Army Medical Research & Materiel Command

Thomas P. Bleck, M.D., University of Virginia

Rogene F. Henderson, Ph.D., Lovelace Respiratory Research Institute

Mark A. Kirk, M.D., University of Virginia

Michael Adler, Ph.D., US Army Medical Research Institute of Chemical Defense

Vera L. Trainer, Ph.D., National Oceanic & Atmospheric Administration

COL Gennady E. Platoff, Ph.D., US Army Medical Research Institute of Chemical Defense

Gary E. Isom, Ph.D., Purdue University

David H. Walker, M.D., University of Texas Galveston

Tony Shih, Ph.D., US Army Medical Research Institute of Chemical Defense

BG Anne L. Sobel, M.D., US Air Force and National Guard

Richard T. Johnson, M.D., Johns Hopkins University

Benedict R. Capacio, Ph.D., US Army Medical Research Institute of Chemical Defense

Lewis Nelson, M.D., NYC Poison Control Center

Paul Greengard, Ph.D., Rockefeller University

COL Jonathan Newmark, M.D., US Army Medical Research Institute of Chemical Defense

Allen A. Fienberg, Ph.D., IntraCellular Therapies, Inc.

Frederic J. Baud, M.D., Universite Paris

Lance L. Simpson, Ph.D., Thomas Jefferson University

Brad Leissa, M.D., Deputy Director, Division of Counter-Terrorism, Center for Drug Evaluation and Research, US Food and Drug Administration